Tag Archives: humor

You gotta know when to hold ‘em

I was honored and humbled to speak at the Doctoral Hooding Ceremony last weekend at the University of North Carolina at Chapel Hill. I received my Ph.D. there in 1982. It was great to be back in Chapel Hill, seeing some old friends and making many new ones.

There was also one of those interesting small-world connections: UNC Chancellor Carol Folt is an ecologist. I first met Carol when she was an assistant professor at Dartmouth and I was commuting from Amherst, where I was a postdoc, to Dartmouth, to teach evolution as a sabbatical replacement for one semester. Carol is such a positive person, always smiling, and an energetic chancellor.

Anyhow, I had never given a talk like this before, so it was a challenge to prepare. Here’s what I had to say to new doctorates; maybe some of you will find it useful as well.

~~~ ~~~ ~~~

Let me begin by congratulating all of the new PhDs and recipients of other doctoral degrees. Each of you climbed a mountain that no one before you had ever climbed. That’s what made it a doctorate — your original research leading to new knowledge.

My remarks today are about constancy versus change, and about luck versus skill. They turn out to be core themes in the research I do, and they also have a lot to do with life, including the decisions we make in our professional careers.

Speaking of constancy, some things hardly seem to change. I got my degree here in 1982. And who won the NCAA men’s basketball title that year? Yep, it was the Tar Heels, just like this year.

Of course, there have also been a lot of changes since I was a student. Music, for example. When we went to the bar, we had these awesome communal listening devices, called jukeboxes. You didn’t even need headphones to hear the music.

Kool & the Gang’s “Celebration” was hot then — and it’s still a great song if you’ve got a party tonight! Cross-over country music was big, too.

Kenny Rogers had a hit called “The Gambler”, about advice from an old poker player. You’ve probably heard it. It goes like this:

“You got to know when to hold ‘em, Know when to fold ‘em, Know when to walk away, Know when to run.”

Of course, the song is about life, using poker as a metaphor. Just as in our careers and lives, poker requires making decisions in the face of uncertainty.

I had a lot of very good luck at Carolina. I went to a party where I happened to meet Madeleine, a graduate student in the School of Public Health, who is now my wife.

However, I also faced some difficulties, and while I managed to get through them, they led me to change the direction of my research.

I came to UNC to study ecology, which focuses on species and their interactions in nature. I got interested in biology when I took a non-majors course as an undergraduate at Oberlin College, and I saw the sweep of discoveries from molecular biology to vertebrate evolution.

As I contemplated graduate school, I focused on ecology because it was filled with interesting and unanswered questions that, to my naïve self back then, seemed like they wouldn’t be too hard to study.

Many ecologists are superb naturalists, including Nelson Hairston, my advisor here at Carolina, who loved the salamanders he studied, and who knew their biology inside and out.

Or Charles Darwin, who was fond of beetles. On a collecting trip, he already had two beetles he wanted, one in each hand, when he came upon a third that he also wanted to keep. He was so in love with his beetles that he popped one into his mouth to free up a hand. Well, it turns out that the one he put in his mouth was a bombardier beetle. To escape predators, they combine and squirt out two chemicals in an explosive exothermic reaction. Needless to say, Darwin lost all three of those beetles.*

As a kid, I loved being outdoors, hiking and playing sports. But I wasn’t a naturalist; I didn’t know very much about any particular group of animals or plants. At least partly because of that lack of familiarity with organisms in the wild, my first efforts at doing ecological research were failures.

Let me give one example, because it’s kind of funny — at least in hindsight. I tried to do a field experiment using praying mantises. I reared batches of them in the lab from egg cases, and then released them on small plots with two treatments. I had painstakingly cleared the vegetation around each plot by hand to keep the mantises where I put them. Well, the next time I went to see how they were doing, I couldn’t find a single one! Maybe some birds were watching me when I released the mantises, wondering: “What is this crazy guy doing?” before gobbling them up. I have no idea what happened, but that experiment was a total bust.

With hindsight, I was lucky that this project failed right away. The treatment effect I was looking for would probably not have given a significant outcome, even if the mantises had stayed put. So even failures can sometimes be valuable, by keeping us from wasting time—and by forcing us to change direction.

Maybe some of you had failed projects, too, before you found your bearings. It’s a normal part of science and scholarship, though it’s upsetting when it happens.

I had another project that also failed. But this second failure led me to the study system that became my dissertation, which was about the effects of forest cutting and competition on a certain group of insects, called ground beetles.

I loved being outdoors in the mountains of western North Carolina, although the frequent rainstorms often flooded the traps that I used to catch the beetles, drenching both the beetles and me. But this project, at last, was successful, leading to my dissertation and some papers.

But I also had doubts that this line of research was a good fit for my interests and skills. Maybe some of you are at similar points in your career.

I’m sure some of you have found work that you hope to continue for the rest of your life. If so, that’s terrific and more power to you.

Others of you might be pondering or even planning a change—using your degree and experience, but setting off in a new direction. Maybe not right away, but perhaps keeping an eye out for some opportunity that better fits your own skills and interests.

In my case, an exciting opportunity dawned in a graduate reading group, when we read a paper about the coevolution of bacteria and viruses that attack bacteria. Even though I had no experience in microbiology, I wrote the head of that lab with an idea for a project related to the paper, and—lucky for me—he hired me as a postdoc.

Before I started my new position, I was worried about working in an area where, once again, I had no experience. Well, I soon discovered that I enjoyed the work. I wasn’t good at it right away, but I liked the rhythm of a microbiology lab. Unlike praying mantises, the bacteria stayed put in their flasks. Unlike the beetles in the mountains, there weren’t any rainstorms in the lab. And sometimes you could see the results of an experiment the very next day.

Down the road, there were more hurdles. In my first year of looking for a faculty position, I applied for dozens of jobs. I got one interview and no offers. Meanwhile, the grant that funded my research wasn’t renewed, and I had a growing family to support. I even thought about leaving science — and I would have if Lady Luck hadn’t come through for me yet again.

The grant was renewed on the second try, and in my second year on the job market I got two offers. So I headed out to Irvine, California, where I started a project that continues to this day.

The project is an evolution experiment. In fact, the experiment was set up to address the same themes as my talk today—luck and skill, constancy and change—although in a scientific context, rather than a personal one.

In evolution, genetic mutations are random events, while the process that Darwin discovered—adaptation by natural selection, sometimes called “survival of the fittest”—multiplies the best competitors across the generations. I wanted to see how luck and skill—that is, mutation and selection—would play out if we could watch evolution over and over and over.

So I set up 12 populations of E. coli bacteria, all started from the same genetic stock, and I put them in identical flasks, with identical food, the same temperature, etc.

I wanted to know: Would they all change and adapt in the same way, showing the power of natural selection to shape life? Or would each population evolve along a different path, highlighting the importance of random mutation?

One thing that makes bacteria great for this experiment is that we can freeze samples and then later revive them as living cells. In essence, our freezers are time-travel machines for the bacteria, allowing us to directly compare and even compete bacteria that lived at different times.

You’ve all heard about our close relatives, the Neanderthals, who went extinct about 40,000 years ago. Some of you might know that their DNA has been recovered from fossils, allowing their genomes to be analyzed. It’s even been discovered that most of us have stretches of Neanderthal DNA in our own genomes.

But despite these amazing advances, we don’t really know what the Neanderthals were like and how similar they would be to us, if they were raised in our world. How well would they play chess, or music, or basketball? What topics would they choose for their dissertations? What would they talk about if they were at this podium?

Back to the experiment with bacteria: We’ve seen many parallel changes in the bacteria across the 12 replicate populations, showing that natural selection can sometimes make evolution predictable, despite the randomness of mutation. But we’ve also seen differences emerge, including in one lineage a surprising new ability to grow on a resource that other E. coli cannot use. And using new technologies that didn’t exist when the experiment was started, we’ve sequenced hundreds of genomes to find the mutations in samples from across the generations and populations, allowing us to test the repeatability of evolution at the level of the DNA itself.

I sometimes call it “the experiment that keeps on giving.” I originally intended the experiment to run for 2,000 generations, which would take about a year. Well, today it’s been running for almost 30 years, and the bacteria have been evolving for 67,000 generations.

This experiment keeps on giving because the bacteria keep evolving in interesting and sometimes unexpected ways, and because students bring new questions and ideas to the project. My hope is that it will continue long after I’m gone.

While the experiment gets a lot of nice press and compliments these days, there have been some obstacles along the way, as there always are in life and science.

When the first paper was submitted, one reviewer was very negative and even hostile. That reviewer wrote: “I feel like a professor giving a poor grade to a good student” — ouch! — without any suggestions for how to improve it. In fact, the reviewer even wrote: “This paper has merit and no errors, but I do not like it.” Well, I wasn’t going to fold — I liked the cards in this hand. So I wrote a rebuttal, and the paper was accepted. In fact, it went on to receive the journal’s award for best paper of the year.

A second obstacle was one of my own making. I came across another experimental system that I found fascinating, and still do — artificial life in the form of computer programs that can replicate themselves and evolve. At the time, I thought maybe the long-term experiment with bacteria had run its course. Well, unlike in poker, when you face important decisions in your research and career, you can ask other people for advice. It’s a good thing, because I was able to have my cake and eat it, too. Everyone told me: “Don’t end the experiment with bacteria. It’s too valuable.” So my lab has kept it going and it has continued to be a scientific gold mine.

Along the way, some creationists have criticized our work. Some don’t believe our results, while others believe us but say: “See, they’re still only bacteria” — as though any scientist would expect to see worms or monkeys or whatever emerge from this experiment.

There can be many reasons for misunderstandings between scientists and the public: problems of education, politics, and communication. The third problem — communication — is one that we can strive to overcome by explaining our work not only to our close colleagues, but also to the general public.

A couple of years ago I had a wonderful opportunity to communicate science to a broad public audience. I was asked by the producer of “Through the Wormhole with Morgan Freeman” to do a segment about our research on bacteria for that show.

One of the scenes had me playing poker with a few of my students. It shows how the effect of a random event—a particular card in a game of poker—depends on the context in which it occurs. The same is true in evolution. A particular mutation that might be advantageous in one species could be detrimental or even lethal in another.

Let’s have a look**:

“When there was a Queen and a King of Hearts on the table and you have the 10 and Ace of Hearts in your hand, you are set up to potentially make a Royal Flush, the most powerful hand in poker. All you need is for the final card to be the Jack of Hearts.”

I’ve been lucky in life. I was born to parents who nurtured me. I was born in a nation dedicated to life, liberty, and the pursuit of happiness. And like those of you receiving your degrees today, I was fortunate to get a superb education here at Carolina.

The French scientist Louis Pasteur — who in the 1800s disproved spontaneous generation, invented what we now call pasteurization, and developed the first rabies vaccine — said: “chance favors the prepared mind.”

Thanks to your Carolina education, and the hard work that brought you here today, you have a prepared mind. You will encounter many uncertainties, probably some obstacles, and hopefully some terrific opportunities as the cards of life are dealt to you.

Play them well: Know when to hold them, know when to fold them. And sometimes you won’t really know what to do, so you’ll just have to give it your best shot.

Thank you, and congratulations again to all of you receiving your doctoral degrees today.

~~~ ~~~ ~~~

*This story is told in the autobiographical chapter of The Life and Letters of Charles Darwin, edited by his son Francis Darwin. I should have checked the source instead of relying on my memory, as Darwin says he lost only two of the three beetles.  The details of the bombardier beetle’s chemical defense system were worked out in the 1960s by Thomas Eisner and others.

**Thanks to Tony Lund, who produced the television show, for also making the short clip that I showed in my talk. You can see a longer clip here.

 

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Optimizing the product of the wow factor and the beneficial mutation supply rate

This post follows up on my post from yesterday, which was about choosing a dilution factor in a microbial evolution experiment that avoids the loss of too many beneficial mutations during the transfer bottleneck.

If we only want to maximize the cumulative supply of beneficial mutations that survive dilution, then following the reasoning in yesterday’s post, we would chose the dilution factor (D) to maximize g Ne = (g2) Nmin = (g2) Nmax / (2g), where Nmax is a constant (the final population size) and D = 1 / (2g). Thus, we want to maximize (g2) / (2g) for g > 0, which gives g = ~2.885 and D = ~0.1354, which is in agreement with the result of Wahl et al. (2002, Genetics), as noted in a tweet by Danna Gifford.

The populations would therefore be diluted and regrow by ~7.4-fold each transfer cycle. But as discussed in my previous post, this approach does not account for the effects of clonal interference, diminishing-returns epistasis, and perhaps other important factors. And if I had maximized this quantity, the LTEE would only now be approaching a measly 29,000 generations!

So let’s not be purists about maximizing the supply of beneficial mutations that survive bottlenecks. There’s clearly also a “wow” factor associated with having lots and lots of generations.  This wow factor should naturally and powerfully reflect the increasing pleasure associated with more and more generations.  So let’s define wow = ge, which is both natural and powerful.  Therefore, we should maximize wow (g2) / (2g), which provides the perfect balance between the pleasure of having lots of generations and the pain of losing beneficial mutations during the transfer bottlenecks.

It turns out that the 100-fold dilution regime for the LTEE is almost perfect!  It gives a value for wow (g2) / (2g) of 75.93.  You can do a tiny bit better, though, with the optimal ~112-fold dilution regime, which gives a value of 76.03.

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What Was I Thinking?

The LTEE has run for over 10,000 days and almost 67,000 generations. It’s time to shut it down, as of today.

It’s been a hell of a lot of work, and we have almost nothing to show for it. As some astute commentators have noted around the web, the creatures in the flasks are still just bacteria—creatures, just as they were created.

If you read the first LTEE paper*, you’ll see we predicted the bacteria should become yeast by about 5,000 generations, nematodes at 15,000 generations or so, and fruit flies by 30,000 generations, maybe 35,000 at the outside.

After that, we’d have to stop the experiment anyhow, because we wouldn’t be able to freeze and bring them back alive any longer.

Plus, we’d have to get IRB approval for human experimentation if we ran it much past 50,000 generations.

Well, we’ve given the LTEE all this time, and still … they ’re just bacteria. I guess we’ve proven that Charles Darwin was wrong after all.

As an astute reviewer pointed out when we submitted that first paper, “I feel like a professor giving a poor grade to a good student.”  I should’ve listened and quit way back then. It would’ve saved everyone a lot of time and effort.

Now it’s going to be a hell of a lot of work next week emptying the freezers and autoclaving all those samples.

* Lenski, R. E., M. R. Rose, S. C. Simpson, and S. C. Tadler. 1991. Long-term experimental evolution in Escherichia coli. I. Adaptation and divergence during 2,000 generations. American Naturalist 138: 1315-1341.

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A Birthday Sonnet

This past weekend, I celebrated my 60th birthday with friends and family from all over. One of the roasters was Ben “The Bard” Kerr, a professor at the University of Washington and colleague in the BEACON Center for the Study of Evolution in Action.

Borrowing from another bard, Ben waxed poetic about one of the lineages in the long-term evolution experiment and raised a toast with this Shakespearean flask.

 

Ben Kerr's Skakespearean flask

ODE TO AN LTEE LINEAGE

Shall I compare Ara-3 to a summer’s day?

Thou start more humbly, but sure potentiate.

Rough spins do shake the darling bugs of Rich’s gaze,

And latecomer’s “fleece” hath all to port citrate.

One line’s long-shot passed by eleven lines,

And how was its controlled complex “skin” pinned?

Promoter capture, over some time refined.

By chance, with nature’s arranging force, trimmed.

But thy Cit-minus partner shall not fade

Nor gain possession of the flair of most

C4 shall Cit snag, now spawned by carbon trade

Then on it turns ‘til lines will species now boast

     So long these cells can achieve, so wise to see,

     So long lives this work- and awe is rife, Lenski.

 

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Another Birthday Haiku

As I said in my last post, I just celebrated my 60th birthday with lots of friends and family. Several folks produced new artistic works, including two lovely haikus that celebrate the E. coli long-term evolution experiment.

Here’s one from Mike Wiser, who did his doctoral research on the long-term lines. A highlight of his work was a paper showing that fitness trajectories in these populations tend to follow a power law, which has no upper bound, rather than an asymptotic rectangular, as I had previously assumed.

Living things adapt.
Evolution keeps going.
No peak yet in sight.

 

Power law prediction, 2013

[The power-law model (blue) predicts future fitness gains much more accurately than does the hyperbolic model (red).  Image modified from Wiser et al. (2013, Science 342: 1364-1367) and shown here under the doctrine of fair use.]

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Birthday Haiku

This past weekend I had my 60th birthday. I was delighted to celebrate it with wonderful colleagues, students, friends, and family.

At a dinner roast and toast, everyone sang When We’re Sixty Four (Thousand), a tribute from the E. coli in the LTEE to the People of the Lab. And several friends came up with new contributions at the intersection of science and culture.

This beauty is from Andy Ellington, a professor in the Center for Systems and Synthetic Biology at the University of Texas and a member of the BEACON Center. As background, Andy coauthored a recent paper that helps to elucidate how one LTEE population evolved the novel ability to use citrate.

Without further ado, here’s his haiku …

Citrate just beyond.

Acetate potentiates.

Glucose is all gone.

 

Citrate

[Image of citrate molecule from Wikimedia Commons]

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When We’re Sixty Four (Thousand)

From the E. coli in the LTEE to the People of the Lab

[To be sung along to this Beatles classic]

 

When we get older, losing our fimbriae,

Many years from now,

Will you still be sending us our thiamine,

Birthday greetings, Erlenmeyer wine?

If we were mutants, crazy and fit,

Would that make you snore?

Will you still feed us, will you still freeze us,

When we’re sixty-four?

 

You’ll be older too,

And if you say the word,

We’ll evolve with you.

 

We could be handy, helping your pubs,

When your grants are gone.

You can write a paper by the fireside,

Weekend days give no time to hide.

Colonies growing, dotting the plates,

Who could ask for more?

Will you still feed us, will you still freeze us,

When we’re sixty-four?

 

Every summer you can buy a freezer when the space gets tight,

If it’s not too dear.

Save our clonal mix,

Plus and minus progeny,

Ara One to Six.

 

Keeping the notebook, pipetting each drop,

Track trajectories.

Indicate precisely what you think will change.

Hypothesize, test, unlimited range.

Give us your data, sequence and store,

Evolving evermore.

Will you still feed us, will you still freeze us,

When we’re sixty-four?

 

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